The need for systems that can deliver a drug at a controlled rate of release to an environment of use over a specified period of time is well established.
Devices for the controlled and continuous delivery of an active agent made from microporous materials are known to the prior art. Generally, the agent is embedded in or surrounded by the material and its release therefrom often is adversely influenced by external conditions. For example, U.S. Pat. No. 2,846,057 discloses a device consisting of a porous cellophane wall surrounding sodium fluoride that is released by water flowing into the pores to dissolve and leach it from the device. Controlled release is hard to obtain with this device because release is governed by external conditions and not by the device. That is, the amount of fluoride released changes with the rate of flow of water, with higher rates increasing the amount released, and lower rates decreasing the amount released over time. Similarly, U.S. Pat. No. 3,538,214 discloses a device consisting of drug coated with a film of water insoluble plastic containing a modifying agent that is soluble at a certain pH. When this device is in the gastro-intestinal tract, the modifying agent is partially or fully dissolved from the film by gastro-intestinal fluid to form a porous film. This lets fluid through the film to dissolve the drug and leach it outwards through the pores into the tract. Controlled release is difficult to achieve with this device because the selection of the modifying agent is based on the unknown acid and alkaline state of the gastro-intestinal tract which concomitantly influences pore formation and the exposure of drug to fluid. A similar device is disclosed in U.S. Pat. No. 2,928,770. The device of this patent consists of an outer layer of drug coated onto a porous material having its pores filled with a softened wax that is supposedly removed in the gastrointestinal tract by the alimentary fluid. This device cannot be relied on for controlled release because it too requires in situ pore formation which is dominated by unregulated external conditions and not by the device. The use of pore formers in substantially water impermeable polymers is disclosed in J. Pharm. Sci. 72, p. 772-775 and U.S. Pat. Nos. 4,557,925; 4,244,941; 4,217,898; 3,993,072. These devices release the core components by simple diffusion only and would be subject to environmental agitation.
U.S. Pat. No. 3,957,523 discloses a device which has a pH sensitive pore former in the device wall. U.S. Pat. Nos. 4,309,996; 4,320,759; 4,235,236 disclose devices with a microporous coat containing a swelling polymer as the driving force for delivery of agents. U.S. Pat. Nos. 4,256,108; 4,160,452; 4,200,098 and 4,285,987 disclose devices with pore formers in only one of multiple wall layers. These devices contain a drilled hole through a semipermeable coating which is impermeable to dissolved drugs and solutes. U.S. Pat. No. 4,326,525 is also based on semipermeable membrane technology with a drilled hole acting as exit portal for the drug. This patent discloses the use of buffers which react via proton-transfer or neutralizing reactions with the drug to produce a new drug agent which has different thermodynamic properties from the parent drug.
U.S. Pat. No. 4,755,180 to Ayer describes solubility modulation through use of a plurality of units comprising buffers and osmagents. These buffers and osmagents increase or decrease the solubility of a drug through manipulation of the drug's pH/solubility profile or by competing with the drug for water within the system. Buffers and osmagents, however, would be ineffective in delivery of poorly water-soluble drugs which have no acid-base character.
The usefulness of the above devices would be increased if a device and method were provided to improve the delivery of drugs which have been found to be difficult to incorporate into an osmotic drug delivery module without conversion of the parent drug into a new drug whose stability and toxicology are uncharacterized. Further utility results from methodology which provides for a sustaining of the improvement inducing effect through technology which substantially extends the lifetime of the modulating agent(s).